GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway–related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non–small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC. Cancer Res; 74(21); 1–7. ©2014 AACR.

GMX1778 and its pro-drug GMX1777 represent a new class of cancer drugs that target nicotinamide phosphoribosyltransferase (NAMPT), as a new strategy to interfere with biosynthesis of the key enzymatic co-factor NAD, which is critical for a number of cell functions including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway related genes deoxyuridine triphosphate and dihydrofolate reductase, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with non-squamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate poly-ADP ribose polymerases (PARP) thereby accelerating NAD consumption. Genetic or pharmacologic
blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat non-squamous NSCLC.

We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through a systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single-photon emission computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for noninvasive clinical imaging. Furthermore, the approach compares favorably with accepted and emerging clinical standards, including PET with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer. Cancer Res; 74(20); 1–10. ©2014 AACR.

We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single photon emission-computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for non-invasive clinical imaging. Further, the approach compares favorably to accepted and emerging clinical standards, including positron emission tomography with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer.

In this guest post from her own personal blog, Jane reflects on her choice to get nipple and areola tattoos as part of breast reconstruction following a bilateral prophylactic mastectomy.

For as long as I can remember, I’ve been a straight arrow. Growing up, I kept my room neat, did my homework and chose as my friends similarly minded. I did what I was supposed to do, completed what I started, wore little makeup, didn’t get my ears pierced until middle school, and never, ever considered getting a tattoo.

Fast-forward four decades.

Not much about my personality has changed, but I do have two tattoos, and when they faded to the point that they were nearly invisible, I chose to have them redone. Don’t bother looking for a decorative rosebud on my shoulder, an alluring bird behind my ear or an inspiring phrase in Latin inked down my spine, however. You won’t find any such tattoos on my skin. In fact, it’s not likely that you’ll ever see my tattoos at all.

That’s because I chose to get nipple and areola tattoos as the final step in the reconstruction of my breasts after I had a bilateral prophylactic mastectomy several years ago.

Like Angelina Jolie, I’d tested positive for a BRCA gene mutation, and this genetic defect – which is 10 times more prevalent among Ashkenazi Jews than in the general population – significantly increased my lifetime risk of developing breast, ovarian and several other types of cancer.

I always knew I’d get the tattoos – so much so that I never even considered not getting them, despite my straight-arrow personality. They were a part of the plan from the beginning, relieving me of the need to research and ponder all the options; list the pros and cons of each; and think, rethink and over-think my decision a thousand times. I’d already done all of that in making the choice to have the prophylactic bilateral mastectomy and reconstruction in the first place.

All told, I had three separate surgeries over the course of 18 months.

Individually and collectively, they took a tremendous toll on my body and on me, and the scars – both physical and emotional – remain. Although they continue to heal a bit each day, I’m not sure they’ll ever fade completely.

15 months after the last surgery, my body finally was ready for the tattooing. Once the tattoos healed, I could hardly believe the incredible power they had to transform my transplanted tissue mounds into breasts. For the first time since my mastectomy, my “faux” breasts looked like real breasts, and my body looked complete. More than transforming my breasts or completing my body, my tattoos restored the rest of me – my spirit, my soul, my deepest self – to wholeness.

Although I will never again be the person I was before my BRCA test, I’m still a straight arrow – with tattoos. Every day, they remind me of the strength and courage it took for me to change my life’s course to ensure that my genetics would not dictate my destiny. My tattoos remind me, too, that the path I’m on is the right one for me, that I’m lucky to be where I am, and that the same strength and courage that helped guide me on that journey to wholeness continue to guide me today.

Jane E. Herman, is a BRCA2 mutation carrier and volunteers as an Outreach Coordinator for FORCE: Facing our Risk of Cancer Empowered in New York City and blogs regularly about her BRCA journey and other slices of her life at JanetheWriter Writes…